DESCRIPTION (applicant's abstract): The PI's and other recent studies with the immediate-early gene, c-fos, have shown that this gene is expressed differentially in discrete brain regions in response to sleep and wakefulness. These findings have led to the speculation that c-fos is involved in sleep. If this cascade is compromised, as with the application of c-fos antisense (which blocks new c-Fos protein synthesis), or in animals lacking the c-fos gene (null c-fos), then there should be less sleep. Recent findings using c-fos antisense is consistent with this hypothesis. Our own preliminary data with null c-fos mice also supports this hypothesis. Specifically, we find that null c-fos mice have a 30% reduction in SWS; REM sleep is intact. We have now discovered that another gene, fos-B, that shares 70% homology with c-fos is involved in REM sleep. Mice lacking fos-B (either heterozygote or homozygote with respect to fos-B deletion) have a 40% reduction in REM sleep; wakefulness and SWS are unchanged. These findings suggest that wakefulness, SWS or REM sleep can be influenced by specific genes. Four specific aims will mechanistically test the overall hypothesis that deletion of specific genes affects specific sleep states. Specific aim 1 will test the hypothesis that null c-fos (homozygous, -/-) mice have less SWS, compared to siblings with one (heterozygotes, +/-) or both alleles of the gene (c-fos +/+). Specific aim 2 will test the hypothesis that null c-fos mice sleep less even when the pressure to sleep is increased. Specific aim 3 will determine whether the reduced sleep in null c-fos mice is due to reductions in levels or sensitivity to known somnogens. Specific aim 4 will test the hypothesis that adenosine, a known somnogen, induces c-fos expression and resultant AP-1 binding in the basal forebrain and VLPO of WT but not null c-fos mice. The finding that sleep could be affected at the level of inducible genes is a novel one. This approach is consistent with emerging evidence that certain behaviors are governed by a cascade of cellular events that involve transcription factors. Clearly, a defect in a gene could result in a malformed protein which could result in abnormal sleep, as has been found in fatal familial insomnia, a prion disease. Our findings are applicable to narcolepsy, an inherited sleep disorder characterized by excessive daytime sleepiness, sleep attacks, cataplexy and hypnagogic hallucinations. The PI's studies to date have used c-Fos to identify the neuronal mechanisms generating sleep. To the best of our knowledge no current program is examining transcription factors as playing a role in the disease.